Lab Publications

Unopposed IL-36 Activity Promotes Clonal CD4+ T-Cell Responses with IL-17A Production in Generalized Pustular Psoriasis

J Invest Dermatol. 2018 Jun;138(6):1338-1347. doi: 10.1016/j.jid.2017.12.024. Epub 2017 Dec 27.

Generalized pustular psoriasis is the most severe psoriasis variant. Here we reveal a pathogenic pathway where innate immune dysregulation promotes T-cell−mediated inflammation. [more...]
 

Sex bias in MHC-I-associated shaping of the adaptive immune system

Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2168-2173. doi: 10.1073/pnas.1716146115

Most immune system dysfunctions show strong sex bias: men are more susceptible to many infectious diseases and cancers of non-reproductive organs, whereas autoimmune diseases are much more common in women. Here we analyzed large cohorts of HLA-typed subjects by high-throughput sequencing of T cell receptor chains. We found that identical HLA-molecules may shape the T cell receptor repertoires differently in men and women. [more...]
 

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis.

Ann Neurol. 2016 Aug;80(2):294-300. doi: 10.1002/ana.24715.

We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4-blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T-cell type MS. Quantitative next generation sequencing of T-cell receptor genes revealed distinct oligoclonal CD4(+) and CD8(+) T-cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS. Ann Neurol 2016;80:294-300. [more...]
 

Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins.

Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7864-9. doi: 10.1073/pnas.1522730113.

Oligoclonal band (OCB) antibodies from the cerebrospinal fluid of patients with multiple sclerosis are important diagnostic tools, but their antigens and their role in the pathogenesis were so far unknown. To identify antigens of OCB we developed a new technology that allowed us to produce recombinant antibodies resembling distinct OCB. We identified three target antigens. All of them were ubiquitous intracellular proteins not specific to brain tissue suggesting that at least these OBC were involved in secondary immune reactions, i.e. in removal of cellular debris, rather than attacking autologous tissue in a specific primary immune reaction. [more...]
 

Multiple sclerosis: Molecular mimicry of an antimyelin HLA class I restricted T-cell receptor.

Neurol Neuroimmunol Neuroinflamm. 2016 May 17;3(4):e241. doi: 10.1212/NXI.0000000000000241.

We employed a new antigen search technology to identify target antigens presented by HLA-A*02:01 to the myelin-reactive human T-cell receptor 2D1, which originates from a T-cell clone recognizing proteolipid protein in the context of HLA-A*03:01. [more...]
 

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation.

Proc Natl Acad Sci U S A. 2016 May 24;113(21):E2973-82. doi: 10.1073/pnas.1524924113.

We analyzed the role of natural killer (NK) cells in multiple sclerosis. [more...]
 

CD8(+) T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing.

Nat Commun. 2016 Apr 4;7:11153. doi: 10.1038/ncomms11153.

We analyzed the immunopathology of Rasmussen encephalitis, a rare pediatric epilepsy, by deep sequencing of T cell receptor chains. We identified public T cell clones, i.e. clones that are shared between different patients. This suggests that antigen-driven T cell expansions are a major cause of the lymphocyte attack against brain tissue. [more...]
 

Melanocyte antigen triggers autoimmunity in human psoriasis

J Exp Med. 2015 Dec 14;212(13):2203-12. doi: 10.1084/jem.20151093. Epub 2015 Nov 30.

Using plasmid-encoded combinatorial peptide libraries (Siewert et al 2012), we identified ADAMTSL5 as a melanocyte autoantigen in human psoriasis. ADAMTSL5 is presented in HLA-C*06:02 molecules on melanocytes, which triggers IL-17 production from CD8+ T cells. [more...]
 

Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation

First published online: July 23, 2014, Brain (2014) doi: 10.1093/brain/awu205

Oligoclonal bands in the cerebrospinal fluid are the most important immunological marker of multiple sclerosis. Whereas oligoclonal IgG bands were intensely investigated in the past, little is known about intrathecal IgM antibodies. Using state-of-the-art technologies, including deep sequencing and single-cell PCR, we identified novel features of the intrathecal IgM repertoire. [more...]
 

Target Specificity of an Autoreactive Pathogenic Human γδ-T Cell Receptor in Myositis

J. Biol. Chem. 2012 287: 20986-20995

We identify antigens and the recognition motif of a pathogenic gamma/delta T cell receptor that was isolated from tissue lesions of a patient with polymyositis. [more...]
 

Unbiased identification of target antigens of CD8+ T-cells with combinatorial libraries coding for short peptides

Nat Med. 2012 May;18(5):824-9

We describe an unbiased and generally applicable technology to identify the antigens of MHC class-I restricted T cell receptors. [more...]
 

Inclusion Body Myositis: Laser Microdissection Reveals Differential Up-Regulation of IFN-γ Signaling Cascade in Attacked versus Nonattacked Myofibers

Am J Pathol. 2011 Sep;179(3):1347-59

Using isolated muscle fibers from patients with inclusion body myositis, we identify differentially regulated signaling pathways in fibers that were attacked by T cells. [more...]
 

Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis

Nat Med. 2009 Jun;15(6):626-32

We explain the paradox that transgenic mice which express a T cell receptor against the brain-specific antigen „MOG“, but do not express MOG protein, develop spontaneous disease. [more...]
 

CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery

Brain. 2009 132(Pt 5):1236-46

T cell receptor repertoire analysis reveals persistent autoaggressive CD8+ T cell clones in brain tissue of patients with Rasmussen encephalitis. [more...]
 

Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis

Nat Med. 2008 14(6):688-93

We link proteomes and transcriptomes of B cells from the cerebrospinal fluid of MS patients providing evidence that CSF-resident B cells may produce oligoclonal band antibodies. [more...]
 

Multiple sclerosis: T-cell receptor expression in distinct brain regions

Brain. 2007 130:2789-99

Here, we compare the T cell receptor repertoires in different lesions and normal appearing white matter of MS patients and identify pervasive CD8+ T cell clones. [more...]
 

Reconstitution of paired T cell receptor α- and β-chains from microdissected single cells of human inflammatory tissues

Proc Natl Acad Sci U S A. 2006 103(32):12057-62

We describe a technology to functionally “resurrect” disease-related T cells that belong to expanded clones from frozen patient´s tissue. [more...]
 
 
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Director

Prof. Dr.

Martin Kerschensteiner

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Group Leader

PD. Dr.

Klaus Dornmair

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